Cerebrovascular disorders and neurodegenerative diseases rank as major diseases in middle-aged to elderly persons and their onset is triggered by dysfunction, retraction, degeneration, decrease, necrosis and so forth of neurons in general or specific regions due to ischemia, trauma, aging or etiology which is in most cases unknown for the cause. Drugs currently used against these diseases are nosotropic ones which are called cerebral metabolism activators, cerebral circulation modifiers or neurotransmitting function improvers. The mechanism of action of these drugs remains unknown in many points and they have only proved to be unsatisfactory in clinical therapeutic efficacy.
Cerebral infarctions such as cerebral thrombosis and embolism are classified as cerebrovascular disorders and their onset is triggered by the brain becoming ischemic due to the stenosis of blood vessels, brain thrombi or brain emboli. For the treatment of cerebral infarctions in an acute phase, anti-edema agents such as mannitol which improve post-ischemic cerebral edema, thrombolytic agents such as urokinase which remove occlusive thrombi, microcirculation modifiers such as ozagrel or cerebral metabolism activators such as citicoline. However, these therapeutics are only nosotropic and their efficacy is by no means satisfactory. In the chronic phase of cerebral infarctions, cerebral metabolism activators such as idebenone and bifemelane, cerebral circulation modifiers such as nicardipine and indeloxazine or neurotransmitting function modifiers such as aniracetam and lisuride are used against dyskinesia such as paralysis, affective disorders such as depression, subjective symptoms such as numbness or consciousness disorders such as delirium and although some of them have been found to be effective in achieving transient improvements in mental conditions, they are generally held to have little efficacy.
A recent finding about cerebral damages due to ischemia is that in addition to the mechanism of tissue necrosis due to energy insufficiency caused by the abolishment of oxygen and nutrient supply to the brain, the mechanism by which glutamic acid which plays the role of a principal neurotransmitter at normal time is released excessively to impair neurons in a positive manner is important (a theory called "excitoneurotoxicity"). In addition, the death of neurons caused by glutamic acid is known to include an immediate disorder due to a rapid elevation of intracellular Ca.sup.2+ and a delayed neuronal death that occurs several days after transient cerebral ischemia in gerbils as demonstrated by Kirino et al. in Brain Res., 239, pp. 57-69, 1982. Apoptosis which has recently gained interest as a mechanism for the death of cells has also been shown to be involved in this delayed neuronal death and other death cases of neurons in ischemic neuronal damages (Nitatori et al., J. Neurosci., 15, pp. 1001-1011, 1995).
Under the circumstances and from the viewpoint of the neurotoxicity of glutamic acid, active efforts have been made to develop drugs that relieve the toxicity of glutamic acid. Briefly, glutamic acid receptor blocking compounds such as dizocilpine, selphotel and YM90K and glutamic acid release suppressing lifarizine and BW619C89 have been demonstrated to be effective in experiments with cerebral ischemic animal models and their clinical efficacy is now under review. However, these drugs have encountered the difficulty that their side effects such as hallucination and hypotension become a dose limiting factor, making it impossible to administer sufficient doses to exhibit a neuroprotective effect.
Parkinson's disease which is a neurodegenerative disease is dyskinesia that involves selective degeneration of dopaminergic neurons in nigrostriatal pathway and a marked improvement in symptoms can be effected by a therapy for supplementing a neurotransmitter using L-dopa. However, it is held that the treatment with L-dopa cannot arrest but rather precipitates the progress of the disorders in dopaminergic neurons and no complete curing has been established. Recently, a report has been made to the effect that a neurotrophic factor which has a protective action on dopaminergic neurons was effective in animal models of Parkinson's disease; however, the experiment relied upon the administration of a protein into the brain and lacks clinical feasibility. In addition, it has been pointed out that apoptosis is involved in the death of dopaminergic neurons in Parkinson's disease.
With a view to treating dementia of Alzheimer's type which is a neurodegenerative disease characterized by pathological changes such as the deposition of amyloid senile plaques, the neurofibrillary tangle formation and the atrophy of the cerebrum, the aforementioned drugs administered in the chronic phase of cerebral infarctions are similarly used today and although some of them have been found to be effective in achieving transient improvements in metal conditions, they are generally held to have little efficacy. By analogy from Parkinson's disease and based on the hypothesis that supplementation of acetylcholine might be effective against dementia of Alzheimer's type, acetylcholine esterase inhibitors, acetylcholine agonists and the like have been developed worldwide. However, excepting the only approved case of tetrahydroaminoacridine, there is no drug that was truly established to have clinical efficacy. Thus, as in the case of Parkinson's disease, no method capable of achieving complete curing of dementia of Alzheimer's type has been established and there is no perspective for its possibility. Again, it has been pointed out that apoptosis is involved in the mechanism of neuronal death in dementia of Alzheimer's type.
Accordingly, in addition to the diseases described above, the following may be mentioned as diseases that involve the degeneration, retraction and death of neurons: various diseases accompanying cerebrovascular disorders including cerebral hemorrhages such as hypertensive intracerebral hemorrhage and subarachnoid hemorrhage, transient cerebral ischemic attacks, cerebroarteriosclerosis and their sequela, or neurodegenerative diseases such as amyotrophic lateral sclerosis, Down's syndrome, Huntington chorea and spinal cerebellar degeneration, as well as brain damages at the time of revivification after cardiac arrest, brain dysfunction prior to or after brain surgery, disorders of the nervous system due to hypoxia, hypoglycemia, brain or spinal damage, intoxication with drugs or gases, diabetes mellitus, administration of anti-cancer agents, alcohol and the like, senile dementia and dysmensia. A key to complete curing which is common to these diseases would be to control the neuronal deaths including apoptosis. In other words, compounds capable of controlling neuronal deaths including apoptosis are believed to be very important and useful not only in the treatment/prevention of cerebrovascular disorders, various neurodegenerative diseases or various other diseases that involve the degeneration, retraction and death of neurons but also in improving the pathological conditions and symptoms of these diseases; however, no compounds having the desired action have been disclosed in the prior art.
Under these circumstances, compounds that are highly safe and which suppress neuronal deaths including apoptosis, namely, those compounds which have a neuroprotective action are expected to provide for complete curing of cerebrovascular disorders, various neurodegenerative diseases or various other diseases that involve the degeneration, retraction and death of neurons and in view of their extreme utility, a strong need exists to formulate them as pharmaceuticals.
As benzindole derivatives, Unexamined Published Japanese Patent Application (kokai) No. 310866/1988 discloses polyhydrobenz[c,d]indolesulfonamide derivatives having a platelet aggregating action and it teaches that they can be used in the treatment of thrombosis, thromboembolism and ischemia; Unexamined Published Japanese Patent Application (kohyo) No. 501361/1988 provides a disclosure to the effect that tricyclic compounds having an indole structure providing a dopaminergic action can be used against hypertension and cardiac dysfunction; however, neither patent gives a description of other aspects such as actions on neuronal deaths and a neuroprotective action. Unexamined Published Japanese Patent Application No. 156670/1985 discloses 1,3,4,5-tetrahydrobenz[c,d]indole derivatives having high affinity for serotonin receptors (particularly those of 5-HT.sub.1 type) and teaches that they are useful in the control of CNS diseases (in particular, anxiety, stress, insomnia and depression) or the treatment of cardiovascular and gastrointestinal diseases; again, there is no disclosure about the suppression of neuronal deaths or a neuroprotective action. As for BAY-R-1531 which is one of the compounds disclosed in the latter patent, Bode et al. reported in Stroke, 21, IV-164 to IV-166, 1990 that it was effective for damage to the hippocampus of gerbils after brain ischemia. However, it was also reported that the protective effect of the compound was only recognized at a by far higher dose than the one that caused altered patterns of behavior due to a serotonin-like action. In other words, the prior art of interest teaches a different structure than the compounds of the present invention and it has no disclosure about the action of suppressing neuronal deaths including apoptosis; in addition, if administered at a dose that shows a protective effect in models of neuronal death, the compound develops side effects due to a serotonin receptor agonist action, thus having clinical problems.
So-called "nonsteroid antiinflammatory drugs" are frequently used today as analgesics but they have no practical efficacy against strong pains such as cancer pain and the one associated with herpes zoster. Potent analgesics that are best known today are narcotic analgesics such as morphine; however, these drugs have the problem of causing tolerance and physical or mental dependence and their use is limited. Hence, there still is a strong need for analgesics that are effective and feature high safety.
Further, those compounds which have a capability of centrally lessening the pains accompanying various diseases are believed to be very important not only in the treatment of pains from various diseases of the nervous system caused by various physical or mental abnormalities but also for the purpose of improving the pathological conditions or symptoms of such diseases. Specific examples of the pains include those associated with cancers, diabetic neuropathy, herpes zoster, arthritis, rheumatism, as well as medical or dental surgery. No analgesic compounds like those of the subject application which have a capability of centrally alleviating the pains from various diseases have been disclosed in the prior art.
The benzindole derivatives disclosed in Unexamined Published Japanese Application No. 204479/1990 are agonists for receptors having high affinity for 5-hydroxytryptamine (of 5HT.sub.1 -type) and which mediate the regulation of the central circulatory system to control unilateral headache. However, this patent makes no disclosure of the action of centrally alleviating the pains from various diseases as is achieved by the compounds of the present invention.